(5-benzyloxy-3-indole)-alkanoylamides and preparation thereof



Patented Oct. 26, 1954 (5 -BENZYLOXY-3 JNDOLE) -ALKANOYL- AMIDES ANDPREPARATION THEREOF Merrill E. Specter, Kalamazoo, Mich., assignor toThe Upjohn Company, Kalamazoo, Mich., a

corporation of Michigan No Drawing. Application April 1, 1952, SerialNo. 279,931

20 Claims.

The present invention relates to novel organic compounds, and is moreparticularly concerned with a novel process for the preparation of (5benzyloxy 3 indole) alkanoylamides and with the products thus-produced.

The compounds of the present invention may be represented by theformula:

wherein X represents phenyl, halophenyl, lower alkoxyphenyl, or loweralkylphenyl; Y represents hydrogen, phenyl, halophenyl, loweralkoxyphenyl, or lower alkylphenyl; R1 and R2 represent hydrogen orlower-alkyl; and n is selected from zero and one. Z represents the amidoradical wherein R3 represents hydrogen, and saturated hydrocarbonradicals such as alkyl, cycloalkyl, phenyl, and aralkyl, and R4represents saturated hydrocarbon radicals such as alkyl, cycloalkyl,phenyl, and aralkyl. The secondary and tertiary amido radicals thusrepresented by Z include such radicals as alkylamido, cycloalkylamido,aralkylamido, phenylamido, dicycloalkylamido, diaralkylamido,dialkylamido, diphenylamido, alkyl aralkylamido, alkyl cycloalkylamido,alkyl phenylamido, aralkyl cycloalkylamido, aralkyl. phenylamido, orcycloalkylphenylamido, and Z can also represent a saturatedmonoheterocyclic amido radical selected from five and six atom saturatedmonoheterocyclic amido radicals, including amido radicals such aspiperidid, morpholid, thiomorpholid, pyrrolidid, or the like.

It is an object of the present invention to prepare novel compounds,(5-benzy1oxy-3-indole)-alkanoylamides. It is a further object of thepresent invention to provide a novel process for the preparation of the(5-benzyloxy-3-indole) -alkanoylamides. Other objectsof the inventionwill be apparent to one skilled in the art to which the inventionpertains.

The novel compounds of the present invention are important intermediatesin the preparation of (5 hydroxy 3 indole) -alkylamines. Morespecifically the (5 hydroxy 3 indole) alkylamines include5-hydroxytryptamine, or more briefly named, serotonin, a substance knownto possess powerful vasoconstrictor qualities, and analogs thereof, suchas the 5--hydroxy-3-[2- (N-methylamino) -ethy1] -indole, 5-hydroxy-3-[2- (N-isopropylamino) -ethyl] -indole, and the like, which analogs havealso demonstrated marked vasoconstrictor qualities.

In the preparation of (5-hydroxy-3-indole)- alkylamines, the compoundsof the present invention, the (5-benzyloxy-3-indole)-alkanoylamides, arereduced to the (5-benzyloxy-3-indole) -alkylamines, e. g.,5-benzyloxy-3-[2-(N- benzyl-N-methylamino) -ethyll-indole, by a suitablereducing agent, e. g., lithium aluminum hy- The reduction is usuallyconducted in an organic solvent, e. g., tetrahydrofuran, and after areaction period of from thirty minutes to five hours the(5-benzyloxy-3-indole) -alkylamine free bases are obtained as heavynon-crystalline oils, or in some instances as a crystalline compound.The free base, without isolation, may be reacted with a stoichiometricquantity of an acid, such as hydrochloric, to form the (5-benzyloxy-3-indole)-alky1amine acid addition salt. Similarly a quaternary ammoniumsalt may also be prepared by reacting the tertiary amine free base withan alkyl halide or aralkyl halide. Alternatively the free base may beisolated by removal of the solvent and admixed with a stoichiometricquantity of an acid, e. g., hydrochloric, to form the acid addition saltand similarly the isolated tertiary amine free base may be mixed with analkyl halide to form the quaternary ammonium salt. The reduction of the(5-benzyloxy-3-indole)-alkanoylamides can also be accomplishedcatalytically, in which case platinum is the preferred catalyst.Serotonin and serotonin analogs are prepared from the(5-benzyloxy-3-indole)- alkylamine salts, if the free base is convertedthereto, by reconverting the salt to the free base, and then subjectingthe free base to hydrogenolysis in the presence of a catalyst, such as aten per cent palladium-charcoal catalyst. The hydrogen pressuresemployed for the hydrogenolysis may range from slightly underatmospheric to about two or three atmospheres, although higher pressurescan also be used. Serotonin and the serotonin analogs can then beisolated by filtering to remove the catalyst, and concentrating andevaporating the solvent employed. The isolated serotonin and serotoninanalogs are in some instances obtained as non-crystalline,water-insoluble oils, which may be converted to a more adaptablewater-soluble acid addition salt by reaction with a stoichiometricquantity of acid such as hydrochloric, or by the addition 3 of sulfuricacid and creatinine sulfate, which salt may then be precipitated fromthe mixture by the addition of an appropriate precipitating agent, e.g., acetone is the preferred reagent for the precipitation of theserotonin creatinine sulfate from solution. Similarly quaternaryammonium salts of the tertiary amine serotonin analogs may also beprepared. Alternatively the serotonin and serotonin analog acid additionsalts may be prepared by treating the serotonin or serotonin analogs,without isolation from the reaction mixture, with a stoichio'metricquantity of an acid, or with a mixture of sulfuric acid and creatininesulfate, and ina similar manner an alkyl halide can be employed toprepare quaternary ammonium salts of the tertiary amine serotoninanalogs. An additional alternative method for the preparation of theacid addition salts, or serotonin analog quaternary ammonium salts,involves the direct debenzylation of an alcoholic "solution of" a-(-benzyloxy-3-indole) alkylaminesalt in the presence of the catalystandhydrogen whereafter the serotonin and serotonin analog salts areprecipitated therefrom as indicated-previously. The hydrogenolysis ofthe (5-benzyloxy-3-indole) -alkylamines may also be accomplishedbyreaction with sodium and liquid ammonia.

- According to themethod of the present invention the(5-.-benzyloXy3-indole) -alkanoylamides are prepared by the reaction ofa Grignard reagentrwith a 5 benzyloxyindole represented by the formula:

XOHO

t e l wherein X, v Y and R2 have. the values specified above-to convertthe 5-benzyloxyindole into a Grignard reagent, andnthereafter reactingthe S-benzyloxyindole Grignard reagent with a haloalkanoylamide, such asthe a-haloacetamides, ,e-halopropionamides, or the like, represented bythe general formula:

present invention may be prepared by'the reduc-.

tive cyclization of 5-benzyloxy-B,2-dinitrostyrenes, as more fullydisclosed in my co-pending application, Serial Number 273,149, filedFebruary 23, 1952. The 5-benzyloXy-5,Z-dinitrostyrenes are prepared .bythe dehydration of 5- benzyloxy 2 -'nitro on [1 (1 nitroalkyD] benzylalcohols, as more fully disclosed in my co-pending application, SerialNumber 2'73,- 148, filed February 23,1952. The 5-benzyloxy-.2-nitro-a-ll-(l-nitroalkyl)lbenzyl alcohols are prepared by thecondensation of 5-benzyloxy-2- nitrobenzaldehydes with a 1-nitroalkane,as more 4 fully disclosed in my co-pending application, Serial Number273,147, filed February 23, 1952. The 5-benzyloxy-2-nitrobenzaldehydesare prepared according to the method of Burton [J. Chem. Soc. 1935,1265] or Portmann and Giovannini [Helv. Chim..Acta, 31, 1381 (1948)].

In carrying out the'method of. the present invention, the starting5-benzyloxyindole and Grignard reagent are usually reacted together inthe presence of an organic solvent, diethyl ether and dibutyl #etherbeing preferred, although other organic solvents, suitable for use inGrignard reactions, such as benzene, toluene, or anisole, can also beemployed. In some instances dimethylformamide may also be utilized. For

the Grignard -step a great many Grignard reagents are satisfactory,among them being those prepared from alkyl halides, cycloalkyl halides,arylhalides, and aralkyl halides, the lower-alkyl halides, such asmethyl iodide and ethyl iodide being preferred. The preparation of the5-benzyloxyindole 'Grignard reagent is usually conducted -at theboiling-point of the solvent employed, although Mother temperaturesbetween about zero and 150 degrees centigrade, preferably between aboutzero and degrees centigrade, may also be used, a :longerreaction period.being required in the lower temperature ranges. The resultingS-benzyloxyindole-magnesium halide is then reacted with ahaloalkanoylamide such as the r-haloacetamides, fl-halopropionamides, orthe like, in the presence of the same organic solvent utilized in thepreparation of the Grignard reactant although others may also be usedif-desired. The reaction of the haloalkanoylamide and the5-benzyloxyindolemagnesium halide is usually oonducted at the boilingpoint of the solvent employed, although other temper- 40 atures betweenabout zero and degrees centig-rade, preferably-about 100 degreescentigrade, may also be used. Upon removal of the organic solvent bydistillation, the remaining residue is heated on a steam bath, and aheavy oil is obtained upon cooling. The(fi-benzyloxy-B-indole)'-Ialkanoylamide may then be isolated fromthevoil'as.a crystalline: product. 'In some'instances the(5-benzyloxy-3-indole) -alkanoyl amide .need not be isolated as acrystalline product, inwhich case the oil may be treated 50- directlyWith a' reducing agent to-produce the (5-benzyloxy 3-indole)-alkylamine. one method for the separation of the (5-benzyloxy-3-indole)alkanoylamides from the oil involves the addition of an organic solvent,such as ether, chloroform;.or.benzene,' with ether being preferred, tothe oil,*: and hydrolyzing the rmixture as with dilute acetic acid,whereupon the (5'-benzyloxy- 3-indole) '-'alkanoylamide separates fromthe mixture. .Afterfiltration, theproduct may berecrystallized fromalcohol to a greater degree of purity.

The preparation of the haloalkanoylamides amine'with vigorous stirring,whereupon a heavy precipitate forms and may be removed by filtration.The precipitate is usually washed with several portions of ether and thecombined filtrate then distilledlunder vacuum to remove the solvent. andproduce the. desired haloalkanoylamide.

-Representative haloalkanoylamides which can be reacted with a chosenS-benzyloxyindolemagamide;

nesium halide to produce the desired(-benzyloxy-3-indole)-alkanoylamides include the ahaloacetamides such asthe a-halo-N-alkyl-N- aralkylacetamides, e. g., a-chloro-N-methyl-N-benzylacetamide, a-chloro-N-benzyl-N-isopropylacetamide;a-halo-N,N-dialkylacetamides, e. g., a-chloro-N,N-dimethylacetamide, achloro-N,N dibutylacetamide, a-iodoN,N-diethylacetamide;a-halo-N,N-diaralkylacetamides, e. g., a-ChlOIO- N,N-dibenzylacetamide;a-halo-N,N-dicycloalkylacetamides, e. g., a-chloroN,N-dicyclohexylacetoz halo-a-alkyl-N-alkyl-N-aralkylacetamides, e. g.,a-chloro a methyl-N-methyl-N- benzylacetamide;a-halo-N-aralkyl-N-cycloalkylacetamides, e. g.,1-chloro-N-benzyl-N-cyclohexylacetamide, ocbromo-N-phenethyl-N-cyclopentylacetamide; a-halo-acetylpiperidides, e.g., occhloroacetylpiperidide, and the .B-halopropionamides, e. g.,,B-ch1oro-N,N-diethylpropionamide, fi-iodopropionylpiperidide,.fi-chloro- -methy1-N- methyl N benzylpropionamide, and the like. Othermethods for the preparation of the starting haloalkanoylamides aredisclosed by Buehler et al. [J. Am. Chem. 500., 59, 4211, (1937)],Jacobs et al. [J Biol. Chem., 21, 148 (1915)], or Frericks [Arch. Pharm.241, 218 (1903)].

The following examples will serve to illustrate the process and productsof this invention, but the said invention is not to be considered aslimited thereto.

To a Grignard reagent prepared from 4.25 grams (0.03 mole) of methyliodide and 2.4 grams of magnesium in 200 milliliters of ether was addeda solution of 5.5 grams (0.025 mole) of 5-benzyloxyindole in 200milliliters of ether. After heating under reflux for thirty minutes, themixture was cooled in an ice-bath and a solution of 5.9 grams (0.03mole) of a-chloro-N-benzyl- N -methylacetamide in 200 milliliters ofether was added thereto. The mixture was stirred and the ether removedby distillation, whereafter the reddish gummy residuewas warmed forthree hours on a steam bath. The mixture was cooled and approximately500 milliliters of ether was added,

followed by the addition with vigorous stirring of a solution offivemilliliters of glacial acetic acid and 95 milliliters of Water. Alight colored solid separated from solution, and after standingovernight the product was filtered and recrystallized from isopropanol.The a-3-(5- benzyloxyindole) -N-benzyl-N methylacetamide melted at151-152 degrees centigrade; yield, 7.5 grams (78 percent).

Analysis-Percent calculated for C25H24O2N2: C, 78.13; H, 6.29. Found: C,78.26; H, 6.21.

Example 2.--oc-3-(5-176712ZIZOZII1/i7td0l8) -N,N- dz'benzylacetamide Inessentiallythe same manner as disclosed in Example 1,a-3-(5-benzyloxyindole)-N,N-dibenzylacetamide, having a melting point of156-157 degrees centigrade, is prepared by reacting methyl iodideGrignard reagent with 5-benzyloxyindole, and thereafter reacting the5'-benzyloxyindolemagnesium iodide with ozchloro-N,Ndibenzylacetamide toproduce 11-3- (5 benzyloxyindole) -N,N-dibenzylacetamide in 69 percentyield.

Analysis.-Percent calculated for C31H2BO2N2: C, 80.84; H, 6.13; N, 6.08.Found: C, 80.98; H, 7.17; N, 5.91.

Ewample 3.a-3- (fi-benzyloayindole) -N-benzylacetamz'de In essentiallythe same manner as disclosed in Example 1, (1-3-(5-benzyloxyindole)N-benzylacetamide, having a melting point of -486 degrees centigrade, isprepared by reacting methyl iodide Grignard reagent with5-benzyloxyindole, and thereafter reacting the5-benzyloxyindolemagnesium iodide with a-ChlOIO-N- benzylacetamide toproduce u-3-(5-b611ZY1OXY- indole)-N-benzylacetamide in thirty percentyield.

Analysis-Percent calculated for C'24H22O2N22 'C, 77.77; H, 5.98; N,7.56. Found: C, 77.74, H,

Example 4.a-3-(S-benzyloxy-Z--methylindole) N -methylacetamide Example5.B 3- [5-(para,para'-dimethylbenzhydryloscy) -z'ndole] ,3methyl-N,N-dz'beneylpropz'onamide In essentially the same manner asdisclosed in Example 1, B 3 [5 (para,para'-dimethylbenzhydryloxy)-indolel 6 methyl N ,N dibenzylpropionamide is prepared by reactingethyl iodide Grignard reagent with 5-(para,para'-dimethylbenzhydryloxy)-indole, and thereafter reacting the 5 (para,para'dimethylbenzhydryloxy)- indolemagnesium iodide with B-chloro-B-methyl-N,N-dibenzylpropionamide.

In the same manner the following (5 -benzyloxy-B-indole)-alkanoylamidesare prepared by reacting the selected 5-alkylbenzyloxyindole and Example'6'.a 3 (5-benzhydryloxyindole) -N- benzylacetamide In essentially thesame manner as shown in Example 1, a 3 (5 benzhydryloxyindole) N-benzylacetamide is prepared by reacting methyl iodide Grignard reagentwith 5-benzhydryloxyindole, and thereafter reacting the5-benzhydryloxyindolemagnesium iodide with oc-ChlOI'O-N-benzylacetamide. 4

In the same manner the following (5-benzyloxy-B-indole)-alkanoylamidesare prepared by reacting 5-benzhydryloxyindole with the selectedphenethylactamide, a-s-rs-benzhydryidxy 2 "any-undue) -N-'ben'z'ylN-methylacetamide, ,8-3-

T (-benzhydryloxyindole) e N methyl N-benzyh pro'pi'onami'de, B-3(5-bh2hydryldiryihdole) 3 ethyl-N-mthylpropionamide, and the like.Ekrdinple -7; --'a-3- [5- (pcmgpara dichlorobenzhydryloxy) 2 tiiylz'noZe] --N methyl-N- benzylacemmide 'Inessentiallythe same-manner asshown'in Example 1,

hydryloxy) -2-ethylindolel N-methyl-N-benzylacetamide isprepared byreacting ethyl bromide Grignard reagent-With5-(para,paradichlorobenzhydryloxy) -2-ethylindole, and thereafterreacting the v 55ipara,para" dichlorobenzhydrylmm) {2 ethylindolem'a'gnesium bromide 'with a-iodo-N-methyl-N-benzylacetamide.

' In the'samefmanner the following (5-benzyloxy-3-indole)-a1kanoylamides are prepared by reacting theselected5-halobenzyloxyindole and chosen haloalkanoylaniide: cc-3- [5-(para,p.ara'- dichlorobenzhydryloxy) f. indole] a ethyl- N-'methyhN-benzylacetamide, a 3 ES-(para-iodobenzyloxy) indolel--N,Ndicyclohexylacetamide, p-3- [5 (para,paradichlorobenzhydryloxy)indolel-N-isopropylpropionamide, 13 3 [5- (parabromobenzyloxy )i1'ld018]-ethyl-N'-rnethylpro pionamide, and the like.

' Example 85-3-3- [5- (paramarddimethowybenzhydrylozcy) -indolel-N,N-dibenzylpropionamide 'In' essentially the same manner as shown inExample 1, e 3 5-(para;para-dimethoxybenz hydryloxy) -indole1-N,N-dibenzylpropionamide is prepared by reacting methyl iodideGrrignard reagent with 5-(para',para' dimethoxybenzhydryloxybindole, andthereafter reacting the 5- (para,para dimethoxybenzhydryloxy)indolefmagnesium iodide with B-chloro-NN-dibenzyljpropionamide.

In the same manner the following (B-behzyloxy-3-indole)-'alkanoylamidesare prepared by reacting the selected 5-alkoxybenz'yloxyindole and thechosen haloalkanoylamide: a -3[5- '(p'ara,para' dimethoxybenzhydryloxy)-indolel a-propyl N -'ethyl-N-cyclohexylacetamide, (it-3- '[5- (paramethoxybenzyloxy) -indole] -N,N-dicyclohexylacetamide, a-S- [5-(para-propoxybenzyloxy) indole] -N-benzyl-N-oyclopentylacetamide, a-3-[5- (para-ethoxybenzyloxy) -2-propylindole] 'N-benzylacetamide,a-3-l5-(para,para-dimeth oxybenzhydryloxy) -indole] N,Ndibenzylacetamide, 5-3- [5- (para-ethoxybenzyloxy) -indo1e1-{3-ethyl-N-benzylpropionamide, and the like.

Example 9.-oc-3- (5-benzyloxyz'ndole) -N-benzyl- N -z'sopropylacetamideIn essentially the same manner as shown in Example 1,w-3-(5-benzyloxyindole) -N-benzyl- N-isopropylacetamide isprepared byreacting methyl iodide Grignard reagent with 5-benzyloz iyindole, andthereafter reacting the 5-benzyloxyindolemagnesium iodide witha-chloro-N- ben'zyl-N-isopropylacetamide.

In the same manner the following 5-benzyloxy- 3 indole-alkanoylamidesare prepared by reacting 5-benzyloxyindole and the chosenhaloalkanoylamide: w- 3- (5-benzyloxyindole) -N,N-dibutylaoetamide, cc 3(5 benzyloxyindole) N- ben'zyl-N-cyclohexylacetarnide, and the-like.

oc-3- [5- (para,para -dichlorobenz- 8 'Eaiample --'-10. p-'3-(5-benzylox'yind0le) N,N-diethylpropionamide In essentially the samemanner as shown in Examme 1, ,3 e 3 5 benzyloxyindole) -N,N-dipionamide.

In the same manner the following (5-benzyloxy-3-indole)-alkanoylamidesare prepared by reacting 5-benzoyloxyindole 'with the chosen'dole)'-N-methyl N-benzylpropionamide, p 3-(5- benzyloxyindole) p methylN benzylpropionamide, and the like.

Example 11.-a 3- (S-benzyloxyz'ndole) -acetopiperidide In essentiallythe same manner as disclosed in Example 1,a-3-(5-benzyloxyindole)-acetapiperidide is prepared by reacting methyliodide Grignard' reagent with B-benzyloxyindole, and thereafter reactingthe 5-benzyloxyindolemagnesium iodide with "a-chloracetylpiperidide toproduce or-'3 (5-benzyloxyindole) '-acetopiperidide.

In thesame' manner thefollowing are prepared by utilizing the selected5-benzyloxyindole and the chosen haloalkanoylamide: a-3-(5-benzyl-'oxyi'ndole) oz methyl acetopiperidide, oc3-(5 benzyloxy 2-"etl'iyli'ndole) acetopiperidide, m-S- (5benzyloxyindolmacctopyrrolidide, oz 3 (5 benzyloxyindole)'acetomorpholide, a-3-(5-ben zyloxyindole) -acetothiomorpholide,5-3-(5-benzylo'xyindole) '-propionopi peridide, B 3 (5-benzyloxyindole)-{3-'ethyl propioncpyrrolidide, and

the like.

4 It is to be unders tood thatthe invention is not to be'limited to theexactdetails of operation or exact'compoundsshown and described, asobvious I modifications and equivalents will be apparent to one skilledin the art; and the invention is therefore to be limited only to thescope of the appended claims.

- 1; In aprocess-for the'preparation of a (5- benzyloxy-3-indole)alkanoylamide; the steps of mixing a 5-benzyloxyindole with a Grignardreagent, and reacting the thus-produced 5-benzyloxyindolemagnesium*halide with a haloalkanoylamide selected-from the group consisting ofsecondary and tertiary a-haloacetamides and fi-halopropionamides'toproduce a (5 benzyloxy- -indoie) -alkanoylamide.

2, In aprocess for the'preparation of a (5-benzyloxy-3-indole)-alkanoylamide, the steps of reacting aS-behzyloxyindole having the formula:

wherein-'X- is selected 'fro'm -the' group consisting -'0fphenyl,-halophenyl, lower alkoxyphenyl, and

' lower alkylphenyl; Y is selected fromthe group 4 temperature betweenabout'zero and degrees '"centigrade in the'presence of an organicsolvent,

and reacting the thus-produced 5-benzyloxyindole'ma gnesiunrhalide at atemperature between degrees centigrade with a about zero and 150haloalkanoylamide having the formula:

wherein R1 is selected from the group consisting of hydrogen and loweralkyl, n is selectedfrom the group consisting 10f zero and one, .X1 is ahalogen, and Z is selected from the group consisting of secondary andtertiaryamido radicals,

to produce a (-benzyloxy-3-indole)-alkanoyl-.

aim-@3182 wherein X is selected from the group consisting of phenyl,halophenyl, lower alkoxyphenyl, and lower alkylphenyl, Y is selectedfrom the group consisting of hydrogen, phenyl, halophenyl; loweralkoxyphenyl, and lower alkylphenyl, and R2 is selected from the groupconsisting of hydrogen and lower alkyl, with a Grignard reagent at atemperature between about zero to 150 degrees centigrade in the presenceof an organic solvent, and reacting the thus-produced5-benzyloxyindolemagnesium halide at a temperature between about zeroand 150 degrees centigrade with a haloalkanoylamide having the formula:

wherein X1 is a halogen and Z is a tertiary amldo radical, to produce a(5-benzyloxy-3-indole)-a1- kanoylamide.

4. The process of claim 3 wherein Z is a di- (lower-alkyl) -amidoradical.

5. In a process for the preparation of a (5- benzyloxy 3 indole)alkanoylamide, the steps of reacting a. 5-benzyloxyindole having theformula:

X-OHO- wherein X is selected from the group consisting of phenyl,halophenyl, lower alkoxyphenyl, and lower alkylphenyl, Y is selectedfrom the group consisting of hydrogen, phenyl, halophenyl, loweralkoxyphenyl, and lower alkylphenyl, and R2 is selected from the groupconsisting of hydrogen and lower alkyl, with a Grignard reagent at atemperature between about zero to 150 degrees centigrade in the presenceof an organic solvent, and reacting the thus-produced5-benzoyloxyindolemag'nesium halide at a temperature between about zeroand 150 degrees centigrade with a haloalkanoylamide having the formula:

l-CH2( JZ wherein X1 is a halogen and Z is a secondary amido radical, toproduce a (5-benzy1oxy-3- indole) -alkanoylamide.

6. The process of claim 5 wherein Z is a lower-cycloalkylamido radical.

10 v '7. The process of claim 5 lower-alkylamido radical.

8."In a process for thepreparation of an a-3- wherein Z is a(S-benzyloxyindole) N aralkyl N alkylacetamide, the steps of with aGrignard reagent, an'd then reacting an mixing 5-benzyloxyind01eoc-halo-N-aralkyl-N-alkyl acetamide with the thus-produced5-benzyloxyindolemagnesium halide to produce anu-3-(5-b6l'lZY1OXYiI1dO18)N- aralkyl-N-alkylacetamide.

9. In a process for the preparation of an 11-3- (5 benzyloxyindole) Naralkylacetamide, the steps of mixing 5-benzyloxyindole with a Grignardreagent, and then reacting an ec-hQJO-N- aralkylacetamid'e with thethus-produced 5 benzyloxyindolemagnesium halideto produce an 01-3-(5-benzyloxyindole) -N-aralkylacetamide.

10. In a process for the preparation'of a 5-3 (5 benzyloxyindole)N,N-dialkylpropionamide, the steps of mixing 5-benzyloxyindole with aGrignard reagent, and then reacting a ,B-halo- N,N-dialkylpropionamidewith the thus-produced 5-benzyloxyindolemagnesium halide to produce a,3-3-(5 benzyloxyindole) N,N dialkylpropionamide.

11. A (5 benzyloxy-3-indole) alkanoylamide having the formula:

wherein X is taken from the group consisting of phenyl, halophenyl,lower alkoxyphenyl, and lower alkylphenyl, Y is taken from the groupconsisting of hydrogen, phenyl, halophenyl, lower alkoxyphenyl, andlower alkylphenyl, R1 and. R2 are taken from the group consisting ofhydrogen and lower alkyl, n is selected from the group consisting ofzero and one, and R3 and R4 are taken from the group consisting ofhydrogen, alkyl, cycloalkyl, aralkyl, and phenyl, at least one of R3 andR4 being other than hydrogen, and further members of the group whereinthe radicals R3 and R4 together with the N form a saturatedmonoheterocyclic amido radical selected from the group consisting offive and six atom saturated monoheterocyclic amido radicals.

12. A (5 benzyloxy-3-indo1e) -alkanoy1amide having the formula:

15. A (fi-benzyloxy 3 indole) -alkano ylamide having the formula:

0 H cH2 JN i 11;

wherein X is phenyl, and R4 is a saturated hy drocarbon-mdjcalconjgqigipgmpflgm eyen carhqn atoms inclusive.

a 3 w oxyinqql lvNwmmla atamide. 4 7 V 1'7. 'A (5'-benzy1oxy 3 indqlelalgagoylqmiqg 5 having th orhm wm V wherein X is phenyl, and,Ra=;anB4gne sathurgted hydrocarbon radicals .x vhichf toge'fih q r captain up 5,to fourteen carbon 'atpmginglugiy wherein X @n Y'a qnh yl and R i a wrahydmarb n .r wl q nta ning u to se n 9.3

bo'h' atoms inclusive.

20, a-3%5-benzhydry1gxyindp1e) N benzyl: acetamide.

11. A (5 - BENZYLOXY-3-INDOLE) -ALKANOYLAMIDE HAVING THE FORMULA: